The present invention relates to the treatment and prevention of breast cancer with 4-hydroxy tamoxifen (4-OHT).
Breast cancer constitutes a significant health problem for women in the United States and throughout the world. Despite advances in detection and treatment of the disease, breast cancer remains the second leading cause of cancer-related deaths in women, affecting more than 180,000 women in the United States alone each year. For women in North America, the life-time odds of getting breast cancer are one in eight.
No universally successful method for preventing or treating breast cancer currently exists. Management of the disease relies on a combination of early diagnosis (through routine breast screening procedures) and aggressive treatment, which may include one or more of a variety of treatments such as surgery, radiotherapy, chemotherapy and hormone therapy. These therapies are dangerous, toxic, costly, and often ineffective, especially in the treatment of metastatic disease.
The most commonly prescribed hormonal medication for breast cancer is tamoxifen. It works by blocking the effects of estrogen, which promotes the growth of breast cancer cells. As a treatment for breast cancer, tamoxifen slows or stops the growth of cancer cells that are already present in the body, and helps prevent recurrences and the development of new cancers. Taking tamoxifen for 5 years reduces the risk of recurrence by about half in patients with estrogen receptor positive cancers. Tamoxifen also decreases the incidence of breast cancer involving the opposite breast (contralateral) in both premenopausal and postmenopausal women. Moreover, tamoxifen has recently been found to reduce the incidence of breast cancer in women at high risk of developing this disease.
In spite of its benefits, tamoxifen has significant drawbacks. Its action potentially impacts on every estrogen receptor bearing cell in the body, and, as both an agonist and antagonist, tamoxifen provokes a wide range of systemic effects. These effects increase the risk of endometrial cancer, endometrial hyperplasia and polyps, deep vein thrombosis and pulmonary embolism, changes in liver enzyme levels, and ocular toxicities, including cataracts. Additionally, patients treated with oral tamoxifen reported having hot flashes, vaginal discharge, depression, amenorrhea, and nausea (Ibis, 2002; Fentiman 1986, 1988, 1989).
Due to tamoxifen's drawbacks, some cancer researchers have proposed using 4-hydroxy tamoxifen, a metabolite of tamoxifen, for breast cancer. In in vitro studies, 4-hydroxy tamoxifen inhibits the growth of both normal and cancerous breast cells (Nomura, 1985; Malet, 1988, 2002; Charlier, 1995). Additionally, transdermally delivered 4-hydroxy tamoxifen exhibits an anti-tumor effect on human breast tumors grown subcutaneously in mice (U.S. Pat. No. 5,904,930).
Limited experiments in humans have shown that percutaneously administered 4-hydroxy tamoxifen can concentrate in local breast tumors, with very little systemic distribution (Mauvais-Jarvis, 1986). However, the most extended reported study of this sort, in which patients were treated for three weeks, showed that breast tissue concentrations of 4-hydroxy tamoxifen administered percutaneously remained lower than those observed after oral tamoxifen treatment (Pujol, 1995). Accordingly, the researchers concluded that they could not propose percutaneous 4-hydroxy tamoxifen as an alternative tamoxifen treatment.
Importantly, none of the reported studies regarding 4-hydroxy tamoxifen in humans has evaluated an anti-tumor effect. This failure leaves wide open the most important question—whether percutaneously administered 4-hydroxy tamoxifen actually exerts any effect on breast cancer in humans. Therefore, a strong need still exists for breast cancer treatments and prophylactics that provoke few systemic side effects.